close

Вход

Забыли?

вход по аккаунту

?

Amyloid and tau proteins in cortical brain biopsy and Alzheimer's disease.

код для вставкиСкачать
ORIGINAL ARTICLE
Amyloid and Tau Proteins in Cortical Brain
Biopsy and Alzheimer’s Disease
Ville Leinonen, MD, PhD,1 Anne M. Koivisto, MD, PhD,2,3 Sakari Savolainen, MD, PhD,1
Jaana Rummukainen, MD, PhD,4 Juuso N. Tamminen, MD,1 Tomi Tillgren, MD,1
Sannakaisa Vainikka, MD,1 Okko T. Pyykkö, BM,1 Juhani Mölsä, BM,1
Mikael Fraunberg, MD, PhD,1 Tuula Pirttilä, MD, PhD,2,3 Juha E. Jääskeläinen, MD, PhD,1
Hilkka Soininen, MD, PhD,2,3 Jaakko Rinne, MD, PhD,1 and Irina Alafuzoff, MD, PhD5,6
Objective: Amyloid-b(Ab) aggregates are presumed to be found in the brain at an early stage of Alzheimer’s disease
(AD) but have seldom been assessed by brain biopsy during life in often elderly patients.
Methods: Between 1991 and 2006 we evaluated 468 patients with suspected normal pressure hydrocephalus with
intraventricular pressure monitoring and a right frontal cortical biopsy sample immunostained for Ab and
hyperphosphorylated tau (HPs). Adequate samples and the clinical follow-up data until death or the end of 2008,
available in 433 cases, were reviewed for the clinical signs of dementia, including AD. Logistic regression analysis
was used to analyze whether Ab and/or HPs in the biopsy samples obtained during life predicted development of
cognitive impairment, in particular, AD.
Results: Of the 433 frontal cortical samples, 42 (10%) displayed both Ab and HPs, 144 (33%) Ab only, and 247 (57%)
neither Ab nor HPs. In a median follow-up time of 4.4 years, 94 patients (22%) developed clinical AD. The presence
of both Ab and HPs was strongly associated (odds ratio [OR], 68.2; 95% confidence interval [CI], 22.1–210) and Ab
alone significantly associated (OR, 10.8; 95% CI, 4.9–23.8) with the clinical diagnosis of AD.
Interpretation: This is the largest follow-up study of patients assessed for the presence of Ab and HPs in frontal
cortical brain biopsy samples. 1) The presence of Ab and HPs spoke strongly for the presence or later development
of clinical AD; 2) Ab alone was suggestive of AD; and 3) the absence of Ab and HPs spoke against a later clinical
diagnosis of AD.
ANN NEUROL 2010;68:446–453
A
ccumulation of amyloid-b(Ab) and hyperphosphorylated tau (HPs) in the brain, in predetermined neuroanatomical regions, are considered diagnostic hallmarks of
Alzheimer’s disease (AD).1,2 Currently, a neuropathological
assessment of the brain at autopsy is the only method available to confirm Ab and HPs deposits and reach the definite
diagnosis of AD.2,3 Ab aggregation is first noted in the cerebral cortex3 and HPs is first seen in the olfactory bulb and
hippocampal formation. HPs and Ab burdens are not always
associated with cognitive impairment,4,5 but their association
with dementia is stronger in younger subjects.6
Criteria for the diagnosis of AD are evolving, with
emphasis on early clinical recognition and multimodal
evaluation using advanced imaging methods and biological markers.7 Clinical dementia of AD is usually preceded by deterioration of episodic memory, and a correct
diagnosis at the mild cognitive impairment (prodromal
AD) phase would lengthen the window for potential
mechanism-based interventions to inhibit AD pathogenesis.8 The accumulation of Ab is thought to appear years
before the clinically detectable cognitive symptoms, thus
offering a potential window for preclinical diagnosis.8
The diagnosis of prodromal AD requires progressive deterioration of episodic memory detected in clinical
and cognitive evaluation as well as AD-related changes in
the brain imaging9,10 or in cerebrospinal fluid (CSF)
View this article online at wileyonlinelibrary.com. DOI: 10.1002/ana.22100
Received Dec 3, 2009, and in revised form Apr 22, 2010. Accepted for publication May 20, 2010.
Address correspondence to Leinonen, Department of Neurosurgery, Kuopio University Hospital, P.O. Box 1777, FIN-70211 Kuopio, Finland.
E-mail: ville.leinonen@kuh.fi
From the 1Department of Neurosurgery, Kuopio University Hospital; 2Unit of Neurology, Institute of Clinical Medicine, University of Eastern Finland;
Department of Neurology, Kuopio University Hospital; 4Department of Pathology, Kuopio University Hospital, Kuopio, Finland; 5Unit of Pathology and
Neurology, Department of Clinical Medicine, University of Eastern Finland, Kuopio, Finland; 6Department of Genetics and Pathology, Uppsala University,
Uppsala, Sweden.
3
C 2010 American Neurological Association
446 V
Leinonen et al: Brain Biopsy in AD
biomarkers.7,11–13 Pittsburgh Compound-B (PIB) is a
potential tracer of Ab depositions in the brain,14,15 and
the PIB uptake in positron emission tomography (PET)
has been shown to correlate with Ab in preceding frontal
cortical biopsy samples.16 Brain biopsy has hardly ever
been included in the diagnostics of AD,17 obviously due
to fear of complications in the often elderly patients. The
predictive value of potential surrogate markers for AD in
brain biopsy samples, obtained at the prodromal phase,
remains to be verified.17
Normal pressure hydrocephalus (NPH) is an
uncommon form of dementia, presenting with impaired
gait, cognitive functions, and urinary incontinence in
various combinations together with dilated brain ventricles and obliterated cortical sulci.18,19 Unlike in other
forms of dementia, a CSF shunt may provide prolonged
improvement, depending on the preoperative diagnostic
accuracy.20 The differentiation between NPH and AD
may be difficult when cognitive symptoms are atypical
for AD, motor symptoms dominate, and there is central
atrophy in brain imaging.
Since 1991 our diagnostic work-up of NPH has
included 24-hour intracranial pressure (ICP) monitoring
through an intraventricular catheter and a small frontal
cortical biopsy sample both obtained through a burr hole
under local anesthesia.16,21–24
The objectives of this study were, while investigating a population-based cohort of 433 patients with
suspected NPH, to assess the presence or absence of ADrelated neuropathological lesions in the right frontal cortical samples, and to relate these findings to the final clinical outcome of the patients. The goal was to assess
whether the earlier biopsy findings were related to the
final clinical diagnosis of AD.
Patients and Methods
Patients
The Kuopio University Hospital (KUH) has served solely a
defined catchment population (851,000 in 2006) in Eastern
Finland. The NPH Registry (www.uef.fi/crc/nph) of KUH
Neurosurgery consists of 468 consecutive patients evaluated for
suspected NPH between 1991 and 2006 (Fig),{FIG} fulfilling
the following criteria: 1) Primary examination, performed by a
neurologist, with one to three symptoms suggestive of NPH:
impairment of cognition, gait, or urinary incontinence. 2)
Enlarged I–IV brain ventricles disproportionate to the size of
the sulci of cerebral convexities in computed tomography (CT)
or magnetic resonance imaging (MRI). 3) According to our
routine NPH work-up, a right frontal 12-mm burr hole was
made under local anesthesia and sedation 3 cm from the midline and close to the coronal suture of the skull, through which
4) one to three cylindrical cortical brain biopsies of 2 to 5 mm
October, 2010
in diameter and 3 to 7 mm in length were obtained with biopsy forceps, and 5) a catheter was passed into the right lateral
ventricle for monitoring of intracranial pressure (ICP) for 24
hours.
CLINICAL COURSE OF THE PATIENTS AFTER THE BIOPSY PROCEDURE. Altogether, 219 patients were shunted
based on the results obtained by ICP monitoring. The response
was evaluated clinically at 2 to 3 months after the surgery. In
cases of no improvement in memory, gait, or incontinence, revision of the shunt was performed when needed. Overall, 168
(77%) of the 219 shunted patients improved clinically.
The neurologist also reevaluated the patient after the
intervention, especially in the case of cognitive deterioration, to
reestablish the differential diagnosis of dementia. The clinical
follow-up was continued in local hospitals and health centers.
The time course and nature of the symptoms were systematically registered in the medical records, enabling a retrospective
evaluation of the symptoms and their progression.
RETROSPECTIVE CLINICAL EVALUATION. All available
follow-up data until death (n ¼ 253) or the end of 2008 (n ¼
180) were collected from the archives of all hospitals of the
KUH catchment area. The primary and contributory causes of
all deaths were obtained from the national registries. A questionnaire on the current clinical condition was responded to by
98 (54%) of the 180 study patients still alive in the end of
2008, or by their care givers. The retrospective analysis of these
records was carried out by a neurologist specializing in memory
disorders (A.M.K.), blinded to the cortical biopsy findings, to
find out whether the patients had developed cognitive impairment sufficient for the diagnosis of any form of dementia in a
median follow-up time of 4.4 years (range 0–17). Clinical data
concerning the possible disability in cognitive functions and the
clinical course of symptoms recorded by responsible clinicians
(neurologist, geriatrician, general practitioner, or all) in the hospital records were particularly emphasized. Repeated descriptions of the cognitive status were available from all 433
patients. Mini-Mental State Examinations (MMSE)25 were
made for 301 patients, but only a minority underwent neuropsychological evaluations. All patients underwent a computed
tomography (CT) examination, but not systematic MRI
scanning.
In the present analysis of the clinical course before and
after the biopsy the DSM-IV criteria26 were used for the retrospective diagnosis of dementia. The diagnosis of the AD type
of dementia was ensured or readjusted if the clinical course
from the first symptom until the end of follow-up or death
fulfilled the NINCDS-ADRDA criteria for possible or
probable AD.27
Possible AD was diagnosed in cases of the coexistence of
other disease contribution to cognitive functions (eg, shuntresponded NPH). Probable AD was diagnosed if there were no
other conditions sufficient to influence the patient’s cognition
at the time of the reevaluation and they fulfilled the criteria of
probable AD. The possible and probable AD patients were
pooled for later analysis.
447
ANNALS
of Neurology
Immunohistochemical Staining
The samples were fixed in buffered formalin overnight and
then embedded in paraffin. Consecutive 7-lm thick sections
were stained with hematoxylin-eosin and by immunohistochemical (IHC) methods. Deparaffinized sections were immunostained with monoclonal antibodies directed to Ab(6F/3D,
M0872, Dako, Carpinteria, CA; dilution 1:100; pretreatment
80% formic acid 1 hour) and HPs(AT8, 3Br-3, Innogenetics,
Ghent Belgium; dilution 1:30). The labeling was visualized
with a streptavidin-biotin method (Histostain-Plus Kit, Zymed,
San Francisco, CA) using Romulin 3-amino-9-ethylcarbazole
(Romulin AEC) chromogen (Biocare Medical, Walnut Creek,
CA). The sections were counterstained with Harris’ hematoxylin
(Merck, Darmstadt, Germany), dehydrated, and mounted in
DePex (BDH Laboratory Supplies, Poole, UK). Omission of
the primary antibodies revealed no irrelevant staining.
evaluation and in 28 cases the clinical follow-up data
were insufficient. Of the 433 immunostained right frontal cortical samples, 42 showed Ab and HPs, 144 only
Ab, and 247 neither Ab nor HPs. Patients with Ab were
older (p < 0.05) and more often females (p < 0.05). In
the cases with both Ab and HPs, the MMSE score was
lower (p < 0.05) and memory deficit was the leading
symptom more often than the disturbances in gait and
incontinence (p < 0.001). Of the 433 patients initially
studied for suspected NPH, 94 developed clinical AD in
a median follow-up time of 4.4 years (range 0–17 years)
(Table 1). In the 144 patients with only Ab in their biopsy, the follow-up time did not differ significantly (p ¼
0.21) between those who developed clinical AD (n ¼
48, 4.8 years, range 0–17) and those who did not (n ¼
96, 4.4 years, range 0–15).
Histological Evaluation
The stained sections were evaluated in light microscopy by one
neuropathologist (I.A.). Cellular or neuritic HPs and Ab fleecy,
diffuse, and dense aggregates were sought for within the whole
sample and graded as present or absent.28
Statistical Analysis
Differences between groups were analyzed for continuous variables with analysis of variance and for nominal variables with
the chi-square test. Multivariate logistic regression analysis was
used to analyze the association of Ab and/or HPs in the right
frontal cortical biopsy sample to the final clinical diagnosis of
AD, with the other covariates being age, gender, follow-up
time, and memory deficit as the leading symptom. The SPSS
statistical software (v. 17.0, SPSS, Chicago, IL) was used.
Ab and HPs in Frontal Cortical Biopsy and
Clinical Diagnosis of AD
In the logistic regression analysis of all 433 patients (Table
2), the independent risk factors for AD were clinically registered memory deficit as the leading symptom (odds ratio
[OR], 13), and Ab with HPs(OR, 68) or Ab alone (OR,
11) in the right frontal cortical samples with the absence of
both Ab and HPs as the reference. In the prediction of
AD, Ab together with HPs was specific (98%) but not
sensitive (36%), whereas Ab alone had lower specificity
(69%) but higher sensitivity (87%). The predictive value
was higher in the younger patient group (65 years or less,
n ¼ 95). In the absence of Ab and HPs, only one of the 77
patients developed AD (Table 3).
Ethical Issues
The study was approved by the KUH Research Ethical Committee, the Finnish National Supervisory Authority for Welfare and
Health, and the Finnish Ministry of Social Affairs and Health.
Results
In the series of 468 patients studied for suspected NPH
with 24-hour intraventricular ICP monitoring and a
right frontal cortical biopsy, the management mortality
until 12 months was 0.6%(3/468). Two patients developed an intracerebral hematoma and died at 2 and 8
months, respectively, and one case of fatal ischemic
stroke developed during the ICP monitoring. In addition, one patient developed postoperative bacterial meningitis (0.2%) but did not deteriorate clinically. None of
the patients developed postoperative seizures or other serious complications.
Final Series
The final series consisted of 433 cases (Table 1, Fig 1).
Six biopsy samples proved inadequate for the histological
448
Ab and HPs in Frontal Cortical Biopsy and
Clinical Diagnosis of Other Dementias
Of the 433 patients, 167 developed cognitive impairment
sufficient for the clinical diagnosis of dementia other
than AD. In the logistic regression analysis of the 339
patients who did not develop AD, the only independent
risk factors for dementia were the clinically registered
memory deficit as the leading symptom (OR, 5.1; 95%
confidence interval [CI], 2.5–11; p < 0.001) and the age
at biopsy (OR/year, 1.08; 95% CI, 1.05–1.12; p <
0.001). Ab alone (OR, 1.1; 95% CI, 0.6–1.9; p ¼ 0.76)
or together with HPs(OR, 0.5; 95% CI, 0.1–2.3; p ¼
0.33) did not predict the development of dementia.
Ab and HPs in Frontal Cortical Biopsy and
Clinical Diagnosis of Mild Cognitive
Impairment (MCI)
Of the 168 patients without clinically diagnosed dementia, 86 had developed some kind of MCI (Ab in 22
[34%]). In the logistic regression analysis of these 168
Volume 68, No. 4
Leinonen et al: Brain Biopsy in AD
TABLE 1: Characteristics of the 433 Patients with Presumed Normal Pressure Hydrocephalus Grouped
According to Amyloid-b(Ab) and Hyperphosphorylated s(HPs) Immunoreactivity in the Frontal Cortical
Biopsy Samples
Immunoreactivitya
Variable
Total
Number of patients
Ab 1 HPs 1
42 (10%)
Ab 1 HPs 2
144 (33%)
Ab 2 HPs 2
247 (57%)
433
Male/female
21/21
54/90
135/112
210/223
Median age at
biopsy years (range)
73 (56–84)
74 (43–87)
70 (25–87)
72 (25–87)
Memory deficit
41
131
208
380
* as the leading symptom
29 (69%)
46 (32%)
50 (20%)
125 (29%)
Gait disturbance
32
126
221
379
Urinary incontinence
21
95
148
264
Median MMSE at
biopsy (range)
19 (9–28)
n ¼ 33
22 (6–29)
n ¼ 102
22 (6–30)
n ¼ 166
22 (6–30)
n ¼ 301
Median follow-up
time years (range)
4.1 (0–12)
4.6 (0–17)
4.5 (0–15)
4.4 (0–17)
Normal pressure
hydrocephalus (shunted)
8
62
149
219
* benefited from shunt
6
46
116
168
Alzheimer’s disease
34 (81%)
48 (33%)
12 (5%)
94 (22%)
* shunted
4
15
7
26
* benefited from shunt
2
11
6
19
Vascular dementia
1
18
34
53
Other specified dementia
2
27
58
87
Unspecified dementia
1
12
19
32c
Symptoms at biopsy
b
Final clinical diagnosis
Immunoreactivity (þ or ) for amyloid-b (Ab) protein (6F/3D monoclonal antibody) and hyperphosphorylated tau (HPs) protein (AT8 monoclonal antibody).
b
Mini-Mental State Examination (MMSE) scores range from 0 to 30, with higher scores indicating better cognitive function.
c
Four patients had two probable diagnoses of dementia.
*Subgroup from above.
a
patients, the only independent factor that was associated
with MCI was the clinically registered memory deficit as
the leading symptom (OR, 12; 95% CI, 1.5–100; p ¼
0.02). Ab alone (OR, 1.0; 95% CI, 0.4–2.1; p ¼ 0.90)
or together with HPs(OR, 1.5; 95% CI, 0.2–9.6; p ¼
0.66) did not predict the development of MCI.
Discussion
In this study of 433 patients with suspected NPH, Ab
was present in the right frontal cortical biopsy in 186
(43%) patients, and 42 (23%) of these 186 patients also
presented HPs. Careful reevaluation of all available cliniOctober, 2010
cal data until death or the end of 2008 showed that 94
(22%) of the 433 patients had developed dementia that
on the basis of clinical data was assigned as AD at the
end of the follow-up time. Immunohistochemically detectable Ab together with HPs in the biopsy was strongly
associated (OR, 68) with the clinical diagnosis of AD.
Furthermore, Ab alone was significantly associated (OR,
11) with the clinical diagnosis of AD.
Of the 144 patients with only Ab in the brain
biopsy, 48 (33%) developed clinical AD during the median follow-up time of 4.4 years, whereas 54 (38%)
developed non-AD dementia and 21 (15%) MCI and 21
(15%) remained cognitively unimpaired. Out of the 247
449
ANNALS
of Neurology
FIGURE: Flowchart of 468 consecutive patients with presumed normal pressure hydrocephalus (NPH) evaluated by right frontal
cortical biopsy. Ab1 indicates immunoreactivity for amyloid-b protein. HPs1 indicates immunoreactivity for hyperphosphorylated
tau protein.
patients without any AD-related lesions, only 12 (5%)
developed AD, whereas 110 (45%) developed non-AD
dementia and 66 (27%) developed MCI, and 59 (24%)
remained cognitively unimpaired. Thus, even without
AD-related lesions the majority (75%) of the patients
developed cognitive impairment when the clinical status
was reviewed from medical records at the end of the
follow-up.
Our results support the concept of preclinical AD,
ie, AD-related pathology in a brain biopsy may predict
AD but not definitely because only 33% of those with
only Ab in the biopsy progressed to clinical AD. Importantly, the presence of Ab did not indicate inevitable cognitive impairment but this should be interpreted cautiously because of the limited follow-up time and because
the majority of the MCI patients had non-AD type
TABLE 2: Logistic Regression Analysis of the Association of Amyloid-b(Ab) and Hyperphosphorylated s(HPs) in
the Cortical Biopsy Samples to the Clinical Diagnosis of Alzheimer’s Disease
Odds Ratio (95% CI)
p
Age at biopsy/year
1.02 (0.98–1.07)
0.31
Follow-up time/year
1.08 (0.98–1.18)
0.12
Covariates
Patients
Female
223
1
Reference
Male
210
1.09 (0.56–2.14)
0.80
shunt-responsive NPH
168
1
Reference
no shunt or shunt-response
265
1.33 (0.64–2.76)
0.44
other than memory deficit
318
1
Reference
memory deficit
115
13.2 (6.7–26.1)
< 0.001
Ab HPs 247
1
Reference
Ab þ HPs 144
10.8 (4.9–23.8)
< 0.001
Ab þ HPs þ
42
68.2 (22.1–210)
< 0.001
NPH
Leading symptom
Ab þ indicates immunoreactivity for amyloid-b protein.
HPs þ indicates immunoreactivity for hyperphosphorylated tau protein.
450
Volume 68, No. 4
Leinonen et al: Brain Biopsy in AD
TABLE 3: Sensitivity, Specificity, Positive Predictive Value (PPV), and Negative Predictive Value (NPV) of
Amyloid-b(Ab) and Hyperphosphorylated s(HPs) in the Cortical Biopsy in the Final Clinical Diagnosis of
Alzheimer’s Disease (n 5 94) in All 433 Patients (A) and in the 95 Patients (n 5 10) Less than 66 Years of Age (B)
Sensitivity
Specificity
PPV
NPV
A
Ab þ
87% (82/94)
69% (235/339)
44% (82/186)
95% (235/247)
HPs þ
36% (34/94)
98% (331/339)
81% (34/42)
85% (331/391)
Ab þ
90% (9/10)
91% (77/85)
53% (9/17)
99% (77/78)
HPs þ
60% (6/10)
100% (85/85)
100% (6/6)
96% (85/89)
B
Ab þ indicates immunoreactivity for amyloid-b protein.
HPs þ indicates immunoreactivity for hyperphosphorylated tau protein.
Numbers in parentheses refer to the corresponding number of cases.
(nonamnestic) MCI. According to autopsy findings, clinically possible AD is heterogeneous and often a mixed
disorder.29 In line with this, some of our patients with
non-AD dementia displayed AD-related pathological
changes. Second, some of the AD patients may have concomitant vascular, Lewy body, or even Tar DNA binding
protein-43 pathology distorting the clinical presentation.
The presence of Ab seems to be fairly sensitive for
AD because only a few Ab-negative patients developed
AD; however, the specificity was rather low. On the contrary, Ab together with HPs was very specific but notably insensitive. Patients with both Ab and HPs probably
had more severe cognitive symptoms, ie, they were at an
advanced disease at the time of biopsy. This is supported
by the lower MMSE score and an average of 1 year (2.4
vs 1.4 years) longer duration of cognitive symptoms prior
to the biopsy compared to the patients with only Ab.
The follow-up time is important concerning the final
endstage and the 4.4 years, restricted mainly due to the
substantial mortality, is still limited taking into consideration the estimated 10–15 years of the prodromal phase.8
It is noteworthy that the predictive value of Ab and HPs
immunostaining was highest in the patients aged 65 years
or less. This is in line with previous reports indicating
that age influences the association between pathological
features and clinical dementia.6
Golomb et al22 reported that 35 (63%) of 56
patients with cognitive impairment and suspected NPH
displayed AD-related pathology in frontal brain biopsy,
ie, neuritic/diffuse plaques. They used silver stain methods that are less sensitive than the IHC techniques used
here. These studies are not fully comparable due to different patient selection criteria and methodology, but
both clearly indicate that AD-related pathology is frequent in patients with suspected NPH. Out of the 433
October, 2010
biopsied patients, 219 with apparent NPH received a
shunt. Of the 168 (77%) patients who benefited from
the shunt, 52 (31%) displayed AD-related pathology and
13 (25%) of them had developed clinical AD by the end
of the follow-up. Of the 168 patients who benefited
from the shunt, 116 (69%) patients did not display ADrelated pathology, and only six (5%) developed AD. In
conclusion, NPH patients with AD-related pathology in
the brain biopsy may benefit from shunting and biopsy
findings should not prevent shunting when the diagnosis
workup otherwise indicate NPH.
The diagnostics of AD seldom include brain biopsy,
obviously due to fear of complications in often elderly
patients,17 and the lack of available treatment with disease-modifying effects. Only a few studies have reported
the use of brain biopsy as a diagnostic aid, and it has
been concluded that in clinically difficult cases where the
diagnosis cannot be made by standard noninvasive methods, this mode of action might be indicated.17 In addition to hemorrhage and infection, other complications
reported are seizures, particularly when rather large samples including leptomeninges, cortex, and white matter
had been resected.17
Here a small sample of a few millimeters was
obtained through a burr hole made under local anesthesia followed by intraventricular catheter installation and
24-hour ICP monitoring. Our patients did not have any
seizures and the overall complication rate was notably
lower than previously reported,17 probably due to the
smaller size of the biopsy. The applied combined procedure was thus safe and well-tolerated, with 0.6% management mortality and 0.2% rate of bacterial meningitis.
According to autopsy studies, the frontal cortex
assessed here may be a representative location to evaluate
Ab deposits in AD.3 In our pilot series, the absence or
451
ANNALS
of Neurology
presence of Ab aggregates in the frontal cortical biopsy
correlated well with the PIB uptake in PET.16 It is
obvious, however, that the biopsy site in the right frontal
cortex does not always reflect the actual Ab load due to
the rather patchy depositions of Ab in the brain, ie, a
negative biopsy does not definitely exclude Ab alteration
elsewhere in the brain.
The strengths of our study are the large cohort from
a defined catchment area, and no loss of patients during
the follow-up ranging up to 17 years, clinical diagnosis
based on entire history of cognitive symptoms, and a
standardized assessment of the brain biopsy samples.
The main weaknesses of this study are the retrospective approach, the lack of autopsy verification, and
data regarding several factors known to influence the progression of AD such as educational level and apolipoprotein E genotype. Overall, 253 patients have died so far,
but a neuropathological examination of the brain has
been carried out in only 11 cases. Consequently, we are
unable to confirm the clinical diagnosis of AD or other
forms of dementia assigned here.
Symptomatic AD is preceded by a long prodromal
stage and a correct diagnosis at this early phase would
lengthen the window for potential mechanism-based interventions.8 Many potential agents are in clinical trials such
as Ab or tau aggregation inhibitors, Ab vaccination or
anti-Ab antibodies, c-secretase modulators, microtubule
stabilizers, and mitochondrial stabilizers.30 Brain biopsy is
thus an interesting option for validation of noninvasive
methods when a specific pharmacological treatment strategy requiring a firm diagnosis will be available.17
Despite invasiveness and the potential risk of complications, imaging-targeted brain biopsies of a few millimeters in size can be safely obtained from noneloquent
brain areas through a burr hole, under local or general
anesthesia, using a stereotactic frame temporarily fixed to
the skull or nonrigid neuronavigational needle biopsy systems. Brain biopsy, when available, eg, during surgical
procedures for NPH, opens a research window to study
the pathobiologies of the brain, and the obtained data
from the biopsy samples and CSF samples may introduce
new potential surrogate markers for the diseases studied.
However, in clinical practice and trials of AD therapies
even in cases with atypical dementias it should be preferable to make further noninvasive investigations for differential diagnostics.
In conclusion, this is the largest follow-up study of
patients assessed for the presence of Ab and HPs in the
right frontal cortical brain biopsy. The findings were 1)
The concomitant presence of Ab and HPs spoke strongly
for the presence of AD; 2) The presence of Ab only was
suggestive of AD in a subset of patients; and 3) The ab452
sence of Ab and HPs spoke against a later development
of AD.
Acknowledgments
The study was supported by research grants from the
Kuopio University Hospital EVO Fund, Maire TaponenFoundation, the Finnish Medical Foundation, and Emil
Aaltonen Foundation.
We thank Marita Voutilanen, RN, for maintenance
of the Kuopio NPH Registry, Nick Hayward, MSc, for
revision of English language, and the Statistics and Registers of Finland for supplying the certificates of death.
Potential Conflicts of Interest
Nothing to report.
References
1.
Braak H, Braak E. Neuropathological stageing of Alzheimerrelated changes. Acta Neuropathol 1991;82:239–259.
2.
Braak H, Alafuzoff I, Arzberger T, Kretzschmar H, et al. Staging of
Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol 2006;
112:389–404.
3.
Thal DR, Rum U, Orantes M, Braak H. Phases of Ab-deposition in
the human brain and its relevance for the development of AD.
Neurology 2002;58:1791–1800.
4.
Braak H, Braak E. Frequency of stages of Alzheimer-related lesions
in different age categories. Neurobiol Aging 1997;18:351–357.
5.
Ingelsson M, Fukumoto H, Newell KL, et al. Early Abeta accumulation and progressive synaptic loss, gliosis, and tangle formation in
AD brain. Neurology 2004;62:925–931.
6.
Savva GM, Wharton SB, Ince PG, et al. Age, neuropathology, and
dementia. N Engl J Med 2009;360:2302–2309.
7.
Dubois B, Feldman HH, Jacova C, et al. Research criteria for the
diagnosis of Alzheimer’s disease: revising the NINCDS-ADRDA criteria. Lancet Neurol 2007;6:734–746.
8.
Perrin RJ, Fagan AM, Holtzman DM. Multimodal techniques for diagnosis and prognosis of Alzheimer’s disease. Nature 2009;461:
916–922.
9.
Jack CR Jr, Lowe VJ, Weigand SD, et al. Serial PIB and MRI in
normal, mild cognitive impairment and Alzheimer’s disease: implications for sequence of pathological events in Alzheimer’s disease. Brain 2009;132:1355–1365.
10.
Vemuri P, Wiste HJ, Weigand SD, et al. MRI and CSF biomarkers
in normal, MCI, and AD subjects: predicting future clinical change.
Neurology 2009;73:294–301.
11.
Mattsson N, Zetterberg H, Hansson O, et al. CSF biomarkers and
incipient Alzheimer disease in patients with mild cognitive impairment. JAMA 2009;302:385–393.
12.
Tapiola T, Alafuzoff I, Herukka SK, et al. Cerebrospinal fluid bamyloid 42 and tau proteins as biomarkers of Alzheimer-type
pathologic changes in the brain. Arch Neurol 2009;66:382–389.
13.
Visser PJ, Verhey F, Knol DL, et al. Prevalence and prognostic
value of CSF markers of Alzheimer’s disease pathology in patients
with subjective cognitive impairment or mild cognitive impairment
in the DESCRIPA study: a prospective cohort study. Lancet Neurol
2009;8:619–627.
Volume 68, No. 4
Leinonen et al: Brain Biopsy in AD
14.
Klunk WE, Engler H, Nordberg A, et al. Imaging brain amyloid in
Alzheimer’s disease with Pittsburgh Compound-B. Ann Neurol
2004;55:306–319.
23.
Holm A, Savolainen S, Alafuzoff I. Brain biopsy prior to treatment
of Alzheimer’s disease. Minim Invasive Neurosurg 2003;46:
161–164.
15.
Ikonomovic MD, Klunk WE, Abrahamson EE, et al. Post-mortem
correlates of in vivo PiB-PET amyloid imaging in a typical case of
Alzheimer’s disease. Brain 2008;131:1630–1645.
24.
16.
Leinonen V, Alafuzoff I, Aalto S, et al. Assessment of b-amyloid in
a frontal cortical brain biopsy specimen and by positron emission
tomography with carbon 11-labeled Pittsburgh Compound B.
Arch Neurol 2008;65:304–309.
Savolainen S, Hurskainen H, Paljarvi L, et al. Five-year outcome of
normal pressure hydrocephalus with or without a shunt: predictive
value of the clinical signs, neuropsychological evaluation and infusion test. Acta Neurochir (Wien) 2002;144:515–523.
25.
Folstein MF, Folstein SE, McHugh PR. ‘‘Mini-mental state.’’ A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189–198.
17.
Warren JD, Schott JM, Fox NC, et al. Brain biopsy in dementia.
Brain 2005;128:2016–2025.
26.
18.
Devito EE, Pickard JD, Salmond CH, et al. The neuropsychology
of normal pressure hydrocephalus (NPH). Br J Neurosurg 2005;19:
217–224.
American Psychiatric Association. Diagnostic and statistical manual
of mental disorders. 4th ed. Washington, DC: American Psychiatric Association, 1994
27.
McKhann G, Drachman D, Folstein M, et al. Clinical diagnosis
of Alzheimer’s disease: report of the NINCDS-ADRDA Work
Group under the auspices of Department of Health and Human
Services Task Force on Alzheimer’s disease. Neurology 1984;
34:939–944.
28.
Alafuzoff I, Pikkarainen M, Arzberger T, et al. Inter-laboratory comparison of neuropathological assessments of beta-amyloid protein:
a study of the BrainNet Europe consortium. Acta Neuropathol
2008;115:533–546.
29.
Schneider JA, Arvanitakis Z, Leurgans SE, Bennett DA. The neuropathology of probable Alzheimer disease and mild cognitive
impairment. Ann Neurol 2009;66:200–208.
30.
Rafii MS, Aisen PS. Recent developments in Alzheimer’s disease
therapeutics. BMC Med 2009;7:7.
19.
Relkin N, Marmarou A, Klinge P, et al. Diagnosing idiopathic
normal-pressure hydrocephalus. Neurosurgery 2005;57:S4–S16.
20.
McGirt MJ, Woodworth G, Coon AL, et al. Diagnosis, treatment,
and analysis of long-term outcomes in idiopathic normal-pressure
hydrocephalus. Neurosurgery 2005;57:699–705.
21.
22.
Savolainen S, Paljarvi L, Vapalahti M. Prevalence of Alzheimer’s
disease in patients investigated for presumed normal pressure hydrocephalus: a clinical and neuropathological study. Acta Neurochir (Wien) 1999;141:849–853.
Golomb J, Wisoff J, Miller DC, et al. Alzheimer’s disease
comorbidity in normal pressure hydrocephalus: prevalence and shunt
response. J Neurol Neurosurg Psychiatry 2000;68:778–781.
October, 2010
453
Документ
Категория
Без категории
Просмотров
2
Размер файла
135 Кб
Теги
biopsy, tau, cortical, protein, amyloid, disease, brain, alzheimers
1/--страниц
Пожаловаться на содержимое документа